Viruses have caused a great stir in this century. Disease attributed to them such as HSV-1, hepatitis, HIV and AIDS are incurable. Antiviral drug that are in current use could be classified as antipurines, antipyrimidines, antibiotics, natural alkaloids, and enzymes which include Acyclovir (ACV, D1), 9-(1,3-Dihydroxy-2-propoxymethyl) guanine(Ganciclovir, D2, DHPG), Desciclovir(D3), 9-.beta.-D-arabinofuranosyl-9H-purin-6-amine(Vidarabine, Ara-A, D4), 2',3'-Dideoxyadnosine (2',3'-Dideoxy-9-.beta.-ribofuranosyl-9H-purine-6-amine, DDA, D6), Carbovir(D5),2',3'-Dideoxyinosine(DDI, D7), 1-(3-Hydroxy-2-phosphonylmethoxylpropyl) -adenosine (HPMPA, D10), Cordycepin(D8), Deoxyguanosine(D9), Cytarabine(D11), 3'-Azido-3'-deoxythymidine(Zidovudine, AZT, ZDV, D13), 2', 3'-Didehydro-3'-deoxythymidine(d4t, D14), 5-Iodo-2'-deoxy-cytidine(IDC, D18), Deoxythymidine(D15), 2'-Fluoro-5-iodo-aracytosine (FIAC, D17), Bromovinyldeoxyuridine (BVDU, D16), 1-.beta.-D-Arabinofuranosyl thymine(Ara-T, D21), 9-(3-Hydroxy-2-phosphonylmethoxylpropyl)cytidine (HPMPC, D22), 5- Ethyl-2.sup.1 -deoxyuridine(EDU, D19), 5-Trifluoro-methyl-2'-deoxy-uridine(F3T, D20), Ribavirin(D23), Riboxamide(D24), Amantadine(D25), Arildone(D28), Rimantidine(D26), Foscamet sodium(D31), Tromantadine(D27), Moroxydine(D29), Enviroxime (D30), and as listed in table 1. They are usually administered orally, topically or parenterally. Their known serious side effects have included central nervous system toxicities and renal dysfunctions.
Structurally, as shown in FIG. 1. ACV(D1) is an analogy of deoxyguanosine with an acyclic carbohydrate moiety. It is active agonist HSV 1, HSV 2, Varicella Zoster virus(VZV), Epstein Barr virus(EBV), and Cytomegalovirus(CMV), especially HSV 1. In vivo studies rated ACV better than FIAC(D17) and DHPG(D2) to treat HSV. It is also better than bromovinyldeoxy uridine(D16) being effective against both HSV 1 and HSV 2. As for the treatment of VZV the ACV's effectiveness has been controversial, in some case showed that ACV is less effective against CMV as compared with DHPG, Idoxuridine, Trifluridine, orAra-A. It is active against EBV, but only during the productive cycle. The combined clinical use of ACV and interferon in the treatment of CMV is known to be synergistic effective.
The bases commonly employed in ACV ointments are polyethylene glycol(PEG), modification aqueous cream and dimethylsulfoxide(DMSO). Corey, L. et al., reported in 1982 that the absorption of ACV through an HSV-infected skin was minimal after the treatment with a 5% ACV ointment containing PEG as the base, 4-6 times a day for 5-7 consecutive days and the plasma concentration of the drug was below 0.023 mg/L, barely detectable by the method (American J. of Medicine, 73:326-34). In 1986 Freeman, D. L. et al. (J. of Infections Diseases, 153:64-70) compared the flux of ACV from three topical preparations made with different vehicles and found that the one with PEG as the base gave the least flux, while the fluxes from the other two with modification aqueous cream and DMSO as the bases were 8 and 10 times higher, respectively. This demonstrates that the use of different vehicles does make a difference. Recently, Greg, E. et al. (J. Invest. Dermatol. 98:856-63,1992) found in a clinic study that the effect of ACV in the treatment of HSV 1 is actually better with oral administration than with local application. The drug concentration in the skin after local application is 2-3 times lower than after given orally. However, it is still considered safer to give the drug locally Since ACV cannot be effective unless it can penetrate the epidermis into deeper layers, it is highly desirable to find an efficient penetration enhancer for it's local application. The present invention is a formulation that contains such enhancer notably from Chinese medicine herbs and was found to significantly improve the transdermal delivery of a number of antiviral drugs.
A transdermal delivery system is a drug delivery system that releases it's drug slowly and continuously at a controlled rate to the skin upon application. Once released, the drug penetrates the epidermis and enters the micro-circulation, which carries it to the target site for an effect. The advantages of such systems are the ease of use, being relatively safe, and affording the interruption of the medication by simply peeling off or removing from the skin whenever an overdosing is suspected. The total skin surface area of adult is about 2 m2, and micro-circulation constitutes about one third of the general circulation. In recent years, therefore, transdermal delivery of drugs has attracted wide attention as a better way of giving drugs. The design of transdermal delivery systems can usually be such that the side effects generally seen with the administration of conventional dosage forms are minimized.
The performance of the transdermal delivery system, however, is limited by: the physicochemical properties of the drug such as the partition coefficient, concentration, the size and the polarity of the molecule; the components of the system such as the bases with differing polarities, viscosity and strength as solvents; and the physiological as well as pathological conditions of the skin such as the "reservoir" function of the stratum corneum, surface lipids, moisture content, temperature, sites, injuries, cutaneous metabolism etc. Today, the most common problem facing us for the development of such system is the lack of safe and effective substances that can be used as the enhancer for various drugs to be given topically.
In recent years Chinese medicines have made a significant progress are gaining wider acceptation by the public. In 1975, for instance, the Department of Health in Japan agreed to include a total of 210 Chinese medicines in its national health insurance policy. A survey of the formulations that contain the Chinese medicines revealed that a total of 150 formulations have glycyrrhiza radix as it's component, amounting to a frequency of 71.4%. This was followed, in order by: zingiberis rhizoma (42.9%), paeoniae radix (32.9%), cinnamoni cortex et caulis (29.5%), zizyphi fructus (31.9%), and hoelen (35.2%). The Japanese pharmacopoeia 2nd ed. lists 93 formulations, in which glycyrrhiza radix is still the one that appears most frequently. An appearance of other Chinese medicines in similar order is also noticed.
The main constituents of these Chinese medicines are as follows: in glycyrrhizae radix have glycyrrhizin and 18-.beta.-glycyrrhizin acid; in zingiberis rhizoma is .alpha.-pinene, cineole and .beta.-myrcene; in Gleditsia sinensis Lam. Is gledinin, tannins, and gleditschia saponin; in zizyphi fructus is ursolic acid and oleanolic acid; in hoelen is eburicoic acid, dehydroeburicoic acid, 3 .beta.-o-acetyltumulosic acid, 3 .beta.-o-acetyldehydrotumulosic acid, and ergosterol; in paeoniae radix is paeoni-florigenone, tetraundecagalloyl-glucose, oxypaeoniflorin, albiflorin, benzoylpaeoniflorin, (+)-catechin, paeo-niflorin, and procyanidin .beta.-1; in cinnamoni cortex et caulis is cinnzeylanol, anhydrocinnzeylanine, cinnamyl acetate, cinnzeylanine, cinnamaldehyde, anhydrocinnzeylanol, and cinncassiol A.
Some of these constituents which described as above, have some surface active or able to lower the surface tension of the skin, thus facilitating the penetration of the drug into the skin. In vitro studies have proved that the glycyrrhetinic acid, and glycyrrhizin are possess anti-inflammatory property, the former two being also effective against paw swelling.
In 1987, segal, R. et al. discovered (U.S. Pat. No. 4,678,772) that a gel made of 2% glycyrrhizin, 0.1% benzoic acid, and 0.2% IDU can be effectively used orally for the treatment of HSV. In that same year they compared (J. Clinic Pharm, 12:1-7) the therapeutic effectiveness against HSV at the lip and the nose of two products: one is a gel containing 2% glycyrrhizin and IDU, the other a VIRUSON marketed ointment only containing 5% IDU. They fount that the gel not only shortened the healing process, but also reduced the pain. A year after, Touitou, E. et al. reported (Drug Design and Delivery, 3:267-72) that using nude mice's skin in a diffusion study in vitro at 34.degree. C. and 25.degree. C., they were able to show that the fluxes of IDU from the gel were 6 and 20 times higher as compared to the ointment at the respective temperatures, the gel and the ointment being the same ones as used in Segal's study.
For safety, we have screened those Chinese medicine that are largely inert by themselves to be successfully used as enhancers. The present invention comprises such enhancers incorporated, along with an antiviral drug, in topical dosage forms such as sprays, ointments, gels, suspensions, patches or solutions. Among the enhancers thus employed are: any single constituent of the following six herbs: glycyrrhizae radix, zingiberis rhizoma, hoelen, paeoniae radix, zizyphi fructus and cinnamoni cortex et caulis; and other constituent of Chinese medicine show in tab. 2 and tab. 3.